TNF-α-Induce Protein 8–Like 1 Inhibits Hepatic Steatosis, Inflammation, and Fibrosis by Suppressing Polyubiquitination of Apoptosis Signal–Regulating Kinase 1
Hong Wu
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
These authors contributed equally to this work.Search for more papers by this authorXiaolei Xu
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
These authors contributed equally to this work.Search for more papers by this authorAncheng Zheng
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
These authors contributed equally to this work.Search for more papers by this authorWeina Wang
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Search for more papers by this authorLi Mei
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorYue Chen
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorShasha Sun
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorLiujun Jiang
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorYutao Wu
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorYijiang Zhou
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorCorresponding Author
Min Zheng
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Qishan Chen, Ph.D., M.D.
Department of Cardiology
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236114
or
Min Zheng, Ph.D.
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236608
Search for more papers by this authorCorresponding Author
Qishan Chen
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Qishan Chen, Ph.D., M.D.
Department of Cardiology
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236114
or
Min Zheng, Ph.D.
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236608
Search for more papers by this authorHong Wu
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
These authors contributed equally to this work.Search for more papers by this authorXiaolei Xu
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
These authors contributed equally to this work.Search for more papers by this authorAncheng Zheng
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
These authors contributed equally to this work.Search for more papers by this authorWeina Wang
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Search for more papers by this authorLi Mei
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorYue Chen
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorShasha Sun
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorLiujun Jiang
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorYutao Wu
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorYijiang Zhou
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Search for more papers by this authorCorresponding Author
Min Zheng
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Qishan Chen, Ph.D., M.D.
Department of Cardiology
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236114
or
Min Zheng, Ph.D.
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236608
Search for more papers by this authorCorresponding Author
Qishan Chen
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Qishan Chen, Ph.D., M.D.
Department of Cardiology
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236114
or
Min Zheng, Ph.D.
The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases
The First Affiliated Hospital
School of Medicine
Zhejiang University
79 Qingchun Road
Hangzhou 310000, China
E-mail: [email protected]
Tel.: +571-87236608
Search for more papers by this authorAbstract
Background and Aims
Characterized by hepatocyte steatosis, inflammation, and fibrosis, NASH is a complicated process that contributes to end-stage liver disease and, eventually, HCC. TNF-α-induced protein 8–like 1 (TIPE1), a new member of the TNF-α-induced protein 8 family, has been explored in immunology and oncology research; but little is known about its role in metabolic diseases.
Approach and Results
Here, we show that hepatocyte-specific deletion of TIPE1 exacerbated diet-induced hepatic steatosis, inflammation, and fibrosis as well as systemic metabolic disorders during NASH pathogenesis. Conversely, hepatocyte-specific overexpression of TIPE1 dramatically prevented the progression of these abnormalities. Mechanically, TIPE1 directly interacted with apoptosis signal–regulating kinase 1 (ASK1) to suppress its TNF receptor–associated factor 6 (TRAF6)–catalyzed polyubiquitination activation upon metabolic challenge, thereby inhibiting the downstream c-Jun N-terminal kinase and p38 signaling pathway. Importantly, dramatically reduced TIPE1 expression was observed in the livers of patients with NAFLD, suggesting that TIPE1 might be a promising therapeutic target for NAFLD and related metabolic diseases.
Conclusions
TIPE1 protects against hepatic steatosis, inflammation, and fibrosis through directly binding ASK1 and restraining its TRAF6-catalyzed polyubiquitination during the development of NASH. Therefore, targeting TIPE1 could be a promising therapeutic approach for NAFLD treatment.
Supporting Information
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Author names in bold designate shared co-first authorship.
